This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vaginal microbicides and prophylactic vaccines represent two seemingly independent, biology-based approaches to preventing the sexual transmission of HIV-1 to women. In principle, either approach could be effective, and both merit continued support. However, the current generations of microbicides and vaccines have not performed well in efficacy trials over the past few years, suggesting that new approaches to prevention science might be needed. Here, we propose experiments in the non-human primate (NHP) model that are intended to explore the concept that microbicides and vaccines represent not competing but complementary technologies. In a 24 animal pilot study, we demonstrated that a combination microbicide/vaccine worked better at protecting animals from vaginal SIV infection than either used alone. In addition, preliminary results indicate that fewer viruses are transmitted vaginally in microbicide and combination vaccine-microbicide treated animals that controls. In other words, our evidence suggests that a combination vaccine-microbicide strategy might work better than either method could do so alone, which we will continue to test in a series of studies over the next few years in macaques at the TNPRC.